The invention relates to the field of protecting normal cells and tissues from anticipated, planned or inadvertent exposure to ionizing radiation. In particular, the invention relates to radioprotective agents administered to a subject prior to or after exposure to ionizing radiation, such as occurs during anticancer radiotherapy.
Ionizing radiation has an adverse effect on cells and tissues, primarily through cytotoxic effects. In humans, exposure to ionizing radiation occurs primarily through therapeutic techniques (such as anticancer radiotherapy) or through occupational and environmental exposure.
A major source of exposure to ionizing radiation is the administration of therapeutic radiation in the treatment of cancer or other proliferative disorders. Subjects exposed to therapeutic doses of ionizing radiation typically receive between 0.1 and 2 Gy per treatment, and can receive as high as 5 Gy per treatment. Depending on the course of treatment prescribed by the treating physician, multiple doses may be received by a subject over the course of several weeks to several months.
Therapeutic radiation is generally applied to a defined area of the subject""s body which contains abnormal proliferative tissue, in order to maximize the dose absorbed by the abnormal tissue and minimize the dose absorbed by the nearby normal tissue. However, it is difficult (if not impossible) to selectively administer therapeutic ionizing radiation to the abnormal tissue. Thus, normal tissue proximate to the abnormal tissue is also exposed to potentially damaging doses of ionizing radiation throughout the course of treatment. There are also some treatments that require exposure of the subject""s entire body to the radiation, in a procedure called xe2x80x9ctotal body irradiationxe2x80x9d, or xe2x80x9cTBI.xe2x80x9d The efficacy of radiotherapeutic techniques in destroying abnormal proliferative cells is therefore balanced by associated cytotoxic effects on nearby normal cells. Because of this, radiotherapy techniques have an inherently narrow therapeutic index which results in the inadequate treatment of most tumors. Even the best radiotherapeutic techniques may result in incomplete tumor reduction, tumor recurrence, increasing tumor burden, and induction of radiation resistant tumors.
Numerous methods have been designed to reduce normal tissue damage while still delivering effective therapeutic doses of ionizing radiation. These techniques include brachytherapy, fractionated and hyperfractionated dosing, complicated dose scheduling and delivery systems, and high voltage therapy with a linear accelerator. However, such techniques only attempt to strike a balance between the therapeutic and undesirable effects of the radiation, and full efficacy has not been achieved.
For example, one treatment for subjects with metastatic tumors involves harvesting their hematopoietic stem cells and then treating the subject with high doses of ionizing radiation. This treatment is designed to destroy the subject""s tumor cells, but has the side effect of also destroying their normal hematopoietic cells. Thus, a portion of the subject""s bone marrow (containing the hematopoietic stem cells), is removed prior to radiation therapy. Once the subject has been treated, the autologous hematopoietic stem cells are returned to their body.
However, if tumor cells have metastasized away from the tumor""s primary site, there is a high probability that some tumor cells will contaminate the harvested hematopoietic cell population. The harvested hematopoietic cell population may also contain neoplastic cells if the subject suffers from a cancers of the bone marrow such as the various French-American-British (FAB) subtypes of acute myelogenous leukemias (AML), chronic myeloid leukemia (CML), or acute lymphocytic leukemia (ALL). Thus, the metastasized tumor cells or resident neoplastic cells must be removed or killed prior to reintroducing the stem cells to the subject. If any living tumorigenic or neoplastic cells are re-introduced into the subject, they can lead to a relapse.
Prior art methods of removing tumorigenic or neoplastic cells from harvested bone marrow are based on a whole-population tumor cell separation or killing strategy, which typically does not kill or remove all of the contaminating malignant cells. Such methods include leukopheresis of mobilized peripheral blood cells, immunoaffinity-based selection or killing of tumor cells, or the use of cytotoxic or photosensitizing agents to selectively kill tumor cells. In the best case, the malignant cell burden may still be at 1 to 10 tumor cells for every 100,000 cells present in the initial harvest (Lazarus et al., J. Hematotherapy, 2(4):457-66, 1993).
Thus, there is needed a purging method designed to selectively destroy the malignant cells present in the bone marrow, while preserving the normal hematopoietic stem cells needed for hematopoietic reconstitution in the transplantation subject.
Exposure to ionizing radiation can also occur in the occupational setting. Occupational doses of ionizing radiation may be received by persons who job involves exposure (or potential exposure) to radiation, for example in the nuclear power and nuclear weapons industries. There are currently 104 nuclear power plants licensed for commercial operation in the United States. Internationally, a total of 430 nuclear power plants are operating in 32 countries. All personnel employed in these nuclear power plants may be exposed to ionizing radiation in the course of their assigned duties. Incidents such as the Mar. 28, 1979 accident at Three Mile Island nuclear power plant, which released radioactive material into the reactor containment building and surrounding environment, illustrate the potential for harmful exposure. Even in the absence of catastrophic events, workers in the nuclear power industry are subject to higher levels of radiation than the general public.
Military personnel stationed on vessels powered by nuclear reactors, or soldiers required to operate in areas contaminated by radioactive fallout, risk similar exposure to ionizing radiation. Occupational exposure may also occur in rescue and emergency personnel called in to deal with catastrophic events involving a nuclear reactor or radioactive material. For example, the men who fought the Apr. 26, 1986 reactor fire at the Chernobyl nuclear power plant suffered radiation exposure, and many died from the radiation effects. In August 2000, navy and civilian rescue personnel risked exposure to radiation when attempting to rescue the crew of the downed Russian nuclear-powered submarine Kursk. Salvage crews may still face radiation exposure if the submarine""s reactor plant was damaged.
Other sources of occupational exposure may be from machine parts, plastics, and solvents left over from the manufacture of radioactive medical products, smoke alarms, emergency signs, and other consumer goods. Occupational exposure may also occur in persons who serve on nuclear powered vessels, particularly those who tend the nuclear reactors, in military personnel operating in areas contaminated by nuclear weapons fallout, and in emergency personnel who deal with nuclear accidents.
Humans and other animals (such as livestock) may also be exposed to ionizing radiation from the environment. The primary source of exposure to significant amounts of environmental radiation is from nuclear power plant accidents, such as those at Three Mile Island, Chernobyl and Tokaimura. A 1982 study by Sandia National Laboratories estimated that a xe2x80x9cworst-casexe2x80x9d nuclear accident could result in a death toll of more than 100,000 and long-term radioactive contamination of large areas of land.
For example, the estimated number of deaths from the Chernobyl accident is from 8,000 to 300,000, and in the Ukraine alone, over 4.6 million hectares of land was contaminated with varying levels of radiation. Fallout was detected as far away as Ireland, northern Scandinavia, and coastal Alaska in the first weeks after the accident. 135,000 people were evacuated from a 30-mile radius xe2x80x9cdead zonexe2x80x9d around the Chernobyl plant, an area which is still not fit for human habitation. Approximately 1.2 million people continue to live in areas of low-level radiation outside the xe2x80x9cdead-zone.xe2x80x9d
Other nuclear power plant accidents have released significant amounts of radiation into the environment. The Three Mile Island accident was discussed above. In Japan, a cracked pipe leaked 51 tons of coolant water from the Tsuruga 2 nuclear plant in July of 1999. A more serious accident occurred on Sep. 30, 1999 at a uranium reprocessing facility in Tokaimura, Japan, where 69 people received significant radiation exposure. The accident occurred when workers inadvertently started a self-sustaining nuclear chain reaction, causing a release of radiation into the atmosphere. A radiation count of 0.84 mSv/hour (4000 times the annual limit) was detected in the immediate area. Thirty-nine households (150 people) were evacuated and 200 meter radius around the site was declared off-limits. The roads within a 3 kilometer radius of the site were closed and residents within 10 kilometer radius of the site were advised to stay indoors. The Tokaimura xe2x80x9ccriticality eventxe2x80x9d is ranked as the third most serious accidentxe2x80x94behind Three Mile Island and Chernobylxe2x80x94in the history of the nuclear power industry.
Environmental exposure to ionizing radiation may also result from nuclear weapons detonations (either experimental or during wartime), discharges of actinides from nuclear waste storage and processing and reprocessing of nuclear fuel, and from naturally occurring radioactive materials such as radon gas or uranium. There is also increasing concern that the use of ordnance containing depleted uranium results in low-level radioactive contamination of combat areas.
Radiation exposure from any source can be classified as acute (a single large exposure) or chronic (a series of small low-level, or continuous low-level exposures spread over time). Radiation sickness generally results from an acute exposure of a sufficient dose, and presents with a characteristic set of symptoms that appear in an orderly fashion, including hair loss, weakness, vomiting, diarrhea, skin burns and bleeding from the gastrointestinal tract and mucous membranes. Genetic defects, sterility and cancers (particularly bone marrow cancer) often develop over time. Chronic exposure is usually associated with delayed medical problems such as cancer and premature aging. An acute a total body exposure of 125,000 millirem may cause radiation sickness. Localized doses such as are used in radiotherapy may not cause radiation sickness, but may result in the damage or death of exposed normal cells.
For example, an acute total body radiation dose of 100,000-125,000 millirem (equivalent to 1 Gy) received in less than one week would result in observable physiologic effects such as skin burns or rashes, mucosal and GI bleeding, nausea, diarrhea and/or excessive fatigue. Longer term cytotoxic and genetic effects such as hematopoietic and immunocompetent cell destruction, hair loss (alopecia), gastrointestinal, and oral mucosal sloughing, venoocclusive disease of the liver and chronic vascular hyperplasia of cerebral vessels, cataracts, pneumonites, skin changes, and an increased incidence of cancer may also manifest over time. Acute doses of less than 10,000 millirem (equivalent to 0.1 Gy) typically will not result in immediately observable biologic or physiologic effects, although long term cytotoxic or genetic effects may occur.
A sufficiently large acute dose of ionizing radiation, for example 500,000 to over 1 million millirem (equivalent to 5-10 Gy), may kill a subject immediately. Doses in the hundreds of thousands of millirems may kill within 7 to 21 days from a condition called xe2x80x9cacute radiation poisoning.xe2x80x9d Reportedly, some of the Chernobyl firefighters died of acute radiation poisoning, having received acute doses in the range of 200,000-600,000 millirem (equivalent to 2-6 Gy). Acute doses below approximately 200,000 millirem do not result in death, but the exposed subject will likely suffer long-term cytotoxic or genetic effects as discussed above.
Acute occupational exposures usually occur in nuclear power plant workers exposed to accidental releases of radiation, or in fire and rescue personnel who respond to catastrophic events involving nuclear reactors or other sources of radioactive material. Suggested limits for acute occupational exposures in emergency situations were developed by the Brookhaven National Laboratories, and are given in Table 1.
A chronic dose is a low level (i.e., 100-5000 millirem) incremental or continuous radiation dose received over time. Examples of chronic doses include a whole body dose of xcx9c5000 millirem per year, which is the dose typically received by an adult working at a nuclear power plant. By contrast, the Atomic Energy Commission recommends that members of the general public should not receive more than 100 millirem per year. Chronic doses may cause long-term cytotoxic and genetic effects, for example manifesting as an increased risk of a radiation-induced cancer developing later in life. Recommended limits for chronic exposure to ionizing radiation are given in Table 2.
By way of comparison, Table 3 sets forth the radiation doses from common sources.
Chronic doses of greater than 5000 millirem per year (0.05 Gy per year) may result in long-term cytotoxic or genetic effects similar to those described for persons receiving acute doses. Some adverse cytotoxic or genetic effects may also occur at chronic doses of significantly less than 5000 millirem per year. For radiation protection purposes, it is assumed that any dose above zero can increase the risk of radiation-induced cancer (i.e., that there is no threshold). Epidemiologic studies have found that the estimated lifetime risk of dying from cancer is greater by about 0.04% per rem of radiation dose to the whole body.
While anti-radiation suits or other protective gear may be effective at reducing radiation exposure, such gear is expensive, unwieldy, and generally not available to public. Moreover, radioprotective gear will not protect normal tissue adjacent a tumor from stray radiation exposure during radiotherapy. What is needed, therefore, is a practical way to protect subjects who are scheduled to incur, or are at risk for incurring, exposure to ionizing radiation. In the context of therapeutic irradiation, it is desirable to enhance protection of normal cells while causing tumor cells to remain vulnerable to the detrimental effects of the radiation. Furthermore, it is desirable to provide systemic protection from anticipated or inadvertent total body irradiation, such as may occur with occupational or environmental exposures, or with certain therapeutic techniques.
Pharmaceutical radioprotectants offer a cost-efficient, effective and easily available alternative to radioprotective gear. However, previous attempts at radioprotection of normal cells with pharmaceutical compositions have not been entirely successful. For example, cytokines directed at mobilizing the peripheral blood progenitor cells confer a myeloprotective effect when given prior to radiation (Neta et al., Semin. Radiat. Oncol. 6:306-320, 1996), but do not confer systemic protection. Other chemical radioprotectors administered alone or in combination with biologic response modifiers have shown minor protective effects in mice, but application of these compounds to large mammals was less successful, and it was questioned whether chemical radioprotection was of any value (Maisin, J. R., Bacq and Alexander Award Lecture. xe2x80x9cChemical radioprotection: past, present, and future prospectsxe2x80x9d, Int J. Radiat Biol. 73:443-50, 1998). Pharmaceutical radiation sensitizers, which are known to preferentially enhance the effects of radiation in cancerous tissues, are clearly unsuited for the general systemic protection of normal tissues from exposure to ionizing radiation.
We have now found that xcex1,xcex2-unsaturated aryl sulfones, in particular benzyl styryl sulfones, provide significant and selective systemic protection of normal cells from radiation-induced damage in animals. When used in radiotherapy techniques, these compounds also show independent toxicity to cancer cells.
It is an object of the invention to provide compositions and methods for protecting the normal cells and tissues from the cytotoxic and genetic effects of exposure to ionizing radiation, in subjects who have incurred or are at risk of incurring exposure to ionizing radiation. The exposure to ionizing radiation may occur in controlled doses during the treatment of cancer and other proliferative disorders, or may occur in uncontrolled doses beyond the norm accepted for the population at large during high risk activities or environmental exposures.
Thus in one aspect, radioprotective xcex1,xcex2 unsaturated aryl sulfone compounds and pharmaceutical compositions comprising radioprotective xcex1,xcex2 unsaturated aryl sulfone compounds are provided.
In another aspect, a method of treating a subject for cancer or other proliferative disorders is provided, comprising administering to the subject an effective amount of at least one radioprotectant xcex1,xcex2 unsaturated aryl sulfone compound prior to administering an effective amount of ionizing radiation, wherein the radioprotective xcex1,xcex2 unsaturated aryl sulfone compound induces a temporary radioresistant phenotype in the subject""s normal tissue.
In a further aspect, the invention provides a method of safely increasing the dosage of therapeutic ionizing radiation used in the treatment of cancer or other proliferative disorders, comprising administering an effective amount of at least one radioprotective xcex1,xcex2 unsaturated aryl sulfone compound prior to administration of the therapeutic ionizing radiation, which radioprotective compound induces a temporary radioresistant phenotype in the subject""s normal tissue.
In yet another embodiment, the invention provides a method for purging bone marrow of neoplastic cells (such as leukemic cells) or tumor cells which have metastasized into the bone marrow, comprising harvesting bone marrow cells from an individual afflicted with a proliferative disorder, treating the harvested bone marrow cells with an effective amount of at least one xcex1,xcex2 unsaturated arylsulfone, and subjecting the treated bone marrow cells with to an effective amount of ionizing radiation. The harvested cells are then returned to the body of the afflicted individual.
In yet a further aspect, the invention provides a method for treating individuals who have incurred or are at risk for incurring remediable radiation damage from exposure to ionizing radiation. In one embodiment, an effective amount of at least one radioprotective xcex1,xcex2 unsaturated aryl sulfone compound is administered to the subject before the subject incurs remediable radiation damage from exposure to ionizing radiation. In another embodiment, an effective amount of at least one radioprotective xcex1,xcex2 unsaturated aryl sulfone compound is administered to the subject after the subject incurs remediable radiation damage from exposure to ionizing radiation.
The term xe2x80x9csubjectxe2x80x9d includes human beings and non-human animals and, as used herein, refers to an organism which is scheduled to incur, is at risk of incurring, or has incurred, exposure to ionizing radiation.
As used herein, xe2x80x9cionizing radiationxe2x80x9d is radiation of sufficient energy that, when absorbed by cells and tissues, induces formation of reactive oxygen species and DNA damage. This type of radiation includes X-rays, gamma rays, and particle bombardment (e.g., neutron beam, electron beam, protons, mesons and others), and is used for medical testing and treatment, scientific purposes, industrial testing, manufacturing and sterilization, weapons and weapons development, and many other uses. Radiation is typically measured in units of absorbed dose, such as the rad or gray (Gy), or in units of dose equivalence, such as the rem or sievert (Sv). The relationship between these units is given below:             rad      ⁢              xe2x80x83            ⁢      a      ⁢              xe2x80x83            ⁢      n      ⁢              xe2x80x83            ⁢      d      ⁢              xe2x80x83            ⁢      g      ⁢              xe2x80x83            ⁢      r      ⁢              xe2x80x83            ⁢      a      ⁢              xe2x80x83            ⁢      y      ⁢              xe2x80x83            ⁢              (                  G          ⁢                      xe2x80x83                    ⁢          y                )                            1        ⁢                  xe2x80x83                ⁢        rad            =              0.01        ⁢                  xe2x80x83                ⁢        G        ⁢                  xe2x80x83                ⁢        y                        rem      ⁢              xe2x80x83            ⁢      a      ⁢              xe2x80x83            ⁢      n      ⁢              xe2x80x83            ⁢      d      ⁢              xe2x80x83            ⁢      s      ⁢              xe2x80x83            ⁢      i      ⁢              xe2x80x83            ⁢      e      ⁢              xe2x80x83            ⁢      v      ⁢              xe2x80x83            ⁢      e      ⁢              xe2x80x83            ⁢      r      ⁢              xe2x80x83            ⁢      t      ⁢              xe2x80x83            ⁢              (                  S          ⁢                      xe2x80x83                    ⁢          v                )                            1        ⁢                  xe2x80x83                ⁢        rem            =              0.01        ⁢                  xe2x80x83                ⁢        S        ⁢                  xe2x80x83                ⁢        v            
The Sv is the Gy dosage multiplied by a factor that includes tissue damage done. For example, penetrating ionizing radiation (e.g., gamma and beta radiation) have a factor of about 1, so 1 Sv=xcx9c1 Gy. Alpha rays have a factor of 20, so 1 Gy of alpha radiation=20 Sv.
By xe2x80x9ceffective amount of ionizing radiationxe2x80x9d is meant an amount of ionizing radiation effective in killing, or in reducing the proliferation, of abnormally proliferating cells in a subject. As used with respect to bone marrow purging, xe2x80x9ceffective amount of ionizing radiationxe2x80x9d means an amount of ionizing radiation effective in killing, or in reducing the proliferation, of malignant cells in a bone marrow sample removed from a subject.
By xe2x80x9cacute exposure to ionizing radiationxe2x80x9d or xe2x80x9cacute dose of ionizing radiationxe2x80x9d is meant a dose of ionizing radiation absorbed by a subject in less than 24 hours. The acute dose may be localized, as in radiotherapy techniques, or may be absorbed by the subjects entire body. Acute doses are typically above 10,000 millirem (0.1 Gy), but may be lower.
By xe2x80x9cchronic exposure to ionizing radiationxe2x80x9d or xe2x80x9cchronic dose of ionizing radiationxe2x80x9d is meant a dose of ionizing radiation absorbed by a subject over a period greater than 24 hours. The dose may be intermittent or continuous, and may be localized or absorbed by the subject""s entire body. Chronic doses are typically less than 10,000 millirem (0.1 Gy), but may be higher.
By xe2x80x9cat risk of incurring exposure to ionizing radiationxe2x80x9d is meant that a subject may advertantly (such as by scheduled radiotherapy sessions) or inadvertently be exposed to ionizing radiation in the future. Inadvertent exposure includes accidental or unplanned environmental or occupational exposure.
By xe2x80x9ceffective amount of the radioprotective xcex1,xcex2 unsaturated aryl sulfone compoundxe2x80x9d is meant an amount of compound effective to reduce or eliminate the toxicity associated with radiation in normal cells of the subject, and also to impart a direct cytotoxic effect to abnormally proliferating cells in the subject. As used with respect to bone marrow purging, xe2x80x9ceffective amount of the radioprotective xcex1,xcex2 unsaturated aryl sulfone compoundxe2x80x9d means an amount of xcex1,xcex2 unsaturated aryl sulfone compound effective to reduce or eliminate the toxicity associated with radiation in bone marrow removed from a subject, and also to impart a direct cytotoxic effect to malignant cells in the bone marrow removed from the subject.
By xe2x80x9cxcex1,xcex2 unsaturated aryl sulfone compoundxe2x80x9d as used herein is meant a chemical compound containing one or more xcex1,xcex2 unsaturated sulfone groups: 
wherein Q2 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and the hydrogen atoms attached to the xcex1 and xcex2 carbons are optionally replaced by other chemical groups.
By xe2x80x9csubstitutedxe2x80x9d means that an atom or group of atoms has replaced hydrogen as the substituent attached to a ring atom. The degree of substitution in a ring system may be mono-, di-, tri- or higher substitution.
The term xe2x80x9carylxe2x80x9d employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be attached together in a pendent manner or may be fused. Examples include phenyl; anthracyl; and naphthyl, particularly 1-naphthyl and 2-naphthyl. The aforementioned listing of aryl moieties is intended to be representative, not limiting. It is understood that the term xe2x80x9carylxe2x80x9d is not limited to ring systems with six members.
The term xe2x80x9cheteroarylxe2x80x9d by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted, stable, mono- or multicyclic heterocyclic aromatic ring system which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom which affords a stable structure.
Examples of such heteroaryls include benzimidazolyl, particularly 2-benzimidazolyl; benzofuryl, particularly 3-, 4-, 5-, 6- and 7-benzofuryl; 2-benzothiazolyl and 5-benzothiazolyl; benzothienyl, particularly 3-, 4-, 5-, 6-, and 7-benzothienyl; 4-(2-benzyloxazolyl); furyl, particularly 2- and 3-furyl; isoquinolyl, particularly 1- and 5-isoquinolyl; isoxazolyl, particularly 3-, 4- and 5-isoxazolyl; imidazolyl, particularly 2-, -4 and 5-imidazolyl; indolyl, particularly 3-, 4-, 5-, 6- and 7-indolyl; oxazolyl, particularly 2-, 4- and 5-oxazolyl; purinyl; pyrrolyl, particularly 2-pyrrolyl, 3-pyrrolyl; pyrazolyl, particularly 3- and 5-pyrazolyl; pyrazinyl, particularly 2-pyrazinyl; pyridazinyl, particularly 3- and 4-pyridazinyl; pyridyl, particularly 2-, 3- and 4-pyridyl; pyrimidinyl, particularly 2- and 4-pyrimidyl; quinoxalinyl, particularly 2- and 5-quinoxalinyl; quinolinyl, particularly 2- and 3-quinolinyl; 5-tetrazolyl; 2-thiazolyl; particularly 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; thienyl, particularly 2- and 3-thienyl; and 3-(1,2,4-triazolyl). The aforementioned listing of heteroaryl moieties is intended to be representative, not limiting.
According to one embodiment, the xcex1,xcex2 unsaturated aryl sulfone group is a styryl sulfone group: 
wherein the hydrogen atoms attached to the xcex1 and xcex2 carbons are optionally replaced by other chemical groups, and the phenyl ring is optionally substituted.
By xe2x80x9cstyryl sulfonexe2x80x9d or xe2x80x9cstyryl sulfone compoundxe2x80x9d or xe2x80x9cstyryl sulfone therapeuticxe2x80x9d as used herein is meant a chemical compound containing one or more such styryl sulfone groups.
The xcex1,xcex2 unsaturated aryl sulfone radioprotective compounds are characterized by cis-trans isomerism resulting from the presence of a double bond. Stearic relations around a double bond are designated as xe2x80x9cZxe2x80x9d or xe2x80x9cExe2x80x9d. Both configurations are included in the scope of xe2x80x9cxcex1,xcex2 unsaturated aryl sulfonexe2x80x9d: 
According to one embodiment, the xcex1,xcex2 unsaturated aryl sulfone compound is a compound of the formula I: 
wherein:
n is one or zero;
Q1 and Q2 are, same or different, are substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
Preferably, n in formula I is one, that is, the compounds comprise xcex1,xcex2 unsaturated benzylsulfones, e.g. styryl benzylsulfones.
In one preferred embodiment according to formula I, Q1 and/or Q2 are selected from substituted and unsubstituted heteroaryl; for example, (E)-3-furanethenyl-2,4-dichlorobenzylsulfone.
In another preferred embodiment according to formula 1, Q1 and Q2 are selected from substituted and unsubstituted phenyl.
Preferred compounds where Q1 and Q2 are selected from substituted and unsubstituted phenyl comprise compounds of the formula II: 
wherein:
Q1a and Q2a are independently selected from the group consisting of phenyl and mono-, di-, tri-, tetra- and penta-substituted phenyl where the substituents, which may be the same or different, are independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, nitro, cyano, carboxy, hydroxy, phosphonato, amino, sulfamyl, acetoxy, dimethylamino(C2-C6 alkoxy), C1-C6 trifluoroalkoxy and trifluoromethyl.
In one embodiment, compounds of formula II are at least di-substituted on at least one ring, that is, at least two substituents on at least one ring are other than hydrogen. In another embodiment, compounds of formula II are at least trisubstituted on at least one ring, that is, at least three substituents on at least one ring are other than hydrogen.
In one embodiment, the radioprotective compound has the formula III: 
wherein R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, nitro, cyano, carboxy, hydroxy phosphonato, amino, sulfamyl, acetoxy, dimethylamino(C2-C6 alkoxy), C1-C6 trifluoroalkoxy and trifluoromethyl.
According to a particularly preferred embodiment of the invention, the radioprotective compound is according to formula III, and R1 and R2 are independently selected from the group consisting of hydrogen, halogen, cyano, and trifluoromethyl; and R3 and R4 are independently selected from the group consisting of hydrogen and halogen.
According to one sub-embodiment of formula III, the radioprotective xcex1,xcex2 unsaturated aryl sulfone compound is a compound of the formula IIIa, wherein R2 and R4 are other than hydrogen: 
Preferred compounds according to formula IIIa having the E-configuration include, but are not limited to, (E)-4-fluorostyryl-4-chlorobenzylsulfone; (E)-4-chlorostyryl-4-chlorobenzylsulfone; (E)-2-chloro-4-fluorostyryl-4-chlorobenzylsulfone; (E)-4-carboxystyryl-4-chlorobenzyl sulfone; (E)-4-fluorostyryl-2,4-dichlorobenzylsulfone; (E)-4-fluorostyryl-4-bromobenzylsulfone; (E)-4-chlorostyryl-4-bromobenzylsulfone; (E)-4-bromostyryl-4-chlorobenzylsulfone; (E)-4-fluorostyryl-4-trifluoromethylbenzylsulfone; (E)-4-fluorostyryl-3,4-dichlorobenzylsulfone; (E)-4-fluorostyryl-4-cyanobenzylsulfone; (E)-2,4-dichloro-4-chlorobenzylsulfone; (E)-4-fluorostyryl-4-chlorophenylsulfone and (E)-4-chlorostyryl-2,4-dichlorobenzylsulfone.
According to another embodiment, compounds of formula IIIa have the Z configuration wherein R1 and R3 are hydrogen, and R2 and R4 are selected from the group consisting of 4-halogen. Such compounds include, for example, (Z)-4-chlorostyryl-4-chlorobenzylsulfone; (Z)-4-chlorostyryl-4-fluorobenzylsulfone; (Z)-4-fluorostyryl-4-chlorobenzylsulfone; (Z)-4-bromostyryl-4-chlorobenzylsulfone; and (Z)-4-bromostyryl-4-fluorobenzylsulfone.
According to another embodiment, the radioprotective xcex1,xcex2 unsaturated aryl sulfone compound is a compound of the formula IV: 
wherein
R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, halogen, C1-8 alkyl, C1-8 alkoxy, nitro, cyano, carboxy, hydroxy, and trifluoromethyl.
In one embodiment, R1 in formula IV is selected from the group consisting of hydrogen, chlorine, fluorine and bromine; and R2, R3 and R4 are hydrogen. A preferred compound of formula IV is (Z)-styryl-(E)-2-methoxy-4-ethoxystyrylsulfone.
According to yet another embodiment, the radioprotective xcex1,xcex2 unsaturated aryl sulfone compound is a compound of the formula V: 
wherein
Q3, Q4 and Q5 are independently selected from the group consisting of phenyl and mono-, di-, tri-, tetra- and penta-substituted phenyl where the substituents, which may be the same or different, are independently selected from the group consisting of halogen, C1-C8 alkyl, C1-C8 alkoxy, nitro, cyano, carboxy, hydroxy, phosphonato, amino, sulfamyl, acetoxy, dimethylamino(C2-C6 alkoxy), C1-C6 trifluoroalkoxy and trifluoromethyl.
According to one sub-embodiment of formula V, the radioprotective xcex1,xcex2 unsaturated aryl sulfone compound is a compound of the formula Va: 
wherein
R1 and R2 are independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-8 alkoxy, nitro, cyano, carboxyl, hydroxyl, and trifluoromethyl; and
R3 is selected from the group consisting of unsubstituted phenyl, mono-substituted phenyl and di-substituted phenyl, the substituents on the phenyl ring being independently selected from the group consisting of halogen and C1-8 alkyl.
Preferably, R1 in formula Va is selected from the group consisting of fluorine and bromine; R2 is hydrogen; and R3 is selected from the group consisting of 2-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, and 2-nitrophenyl.
A preferred radioprotective styryl sulfone according to formula Va is the compound wherein R1 is fluorine, R2 is hydrogen and R3 is phenyl, that is, the compound 2-(phenylsulfonyl)-1-phenyl-3-(4-fluorophenyl)-2-propen-1-one.
By xe2x80x9cdimethylamino(C2-C6 alkoxy)xe2x80x9d is meant (CH3)2N(CH2)nOxe2x80x94 wherein n is from 2 to 6. Preferably, n is 2 or 3. Most preferably, n is 2, that is, the group is the dimethylaminoethoxy group, that is, (CH3)2NCH2CH2Oxe2x80x94.
By xe2x80x9cphosphonatoxe2x80x9d is meant the group xe2x80x94PO(OH)2.
By xe2x80x9csulfamylxe2x80x9d is meant the group xe2x80x94SO2NH2.
Where a substituent on an aryl nucleus is an alkoxy group, the carbon chain may be branched or straight, with straight being preferred. Preferably, the alkoxy groups comprise C1-C6 alkoxy, more preferably C1-C4 alkoxy, most preferably methoxy.